Anandamide pharmacological properties

Since the discovery of anandamide in 1992, a number of studies have examined its pharmacological properties. Although its roles are still elusive, a plethora of data supports the initial postulate that anandamide is the major endogenous cannabinoid ligand. As mentioned earlier, anandamide binds to CB1 from brain preparations and displaces various well-... 

Pharmacological properties of anandamide - further evidence for an unknown cannabinoid receptor... 

As an example of the application of metabolomics, we will refer to the substrates of the enzyme fatty acyl amide hydrolase (FAAH) that regulates several brain lipids that have interesting pharmacological properties including effects on the control of pain. It is well known that some fatty acyl amides of ethanolamine are substrates of FAAH, such as the ethanolamide of arachidonic acid (anandamide), which is an endogenous ligand of cannabinoid receptors. 

Arachidonic acid ethanolamide (anandamide) and similar compounds are constituents of the brain. Anandamide and certain of the compounds similar with same, bind to the cannabinoid receptor. The binding of the ananamide to the cannabinoid receptor is similar to the binding of A9-tetrahydrocannabinol. There exist in the body many mediators, which are derivatives of arachidonic acid, such as prostaglandins and leukotrienes, which are present as large families of related compounds. Certain of these do not bind to the cannabinoid receptor, and it was one of the aims of the present invention to provide and identify compounds which have pharmacological properties similar to the properties of anandamide. 

Endogenous ligands for the cannabinoid receptor have not yet been identified. Arachidonylethanolamide, a new arachidonic acid derivative named anandamide, was isolated from porcine brain. Its structure was determined by mass spectrometry and nuclear magnetic resonance spectroscopy and was confirmed by synthesis. It inhibits the specific binding of a labelled cannabinoid probe to synaptosomal membranes in a manner typical of competitive ligands, and produces a concentration-dependent inhibition of the electrically-evoked twitch response of the mouse vas deferens, a characteristic effect of psychotropic cannabinoids. Similar compounds were synthesized and their pharmacological properties were investigated. 

Similar conclusions were reached by Howlett and coworkers, who investigated the vasodilator action of anandamide in isolated aortic rings from rabbits (Mukhopadhyay et al. 2002). In those experiments, the vasorelaxant effect of anandamide had a major (80%) endothelium-dependent and a minor endothelium-independent component, thus making it an attractive model for further exploration of the pharmacological properties of the endothelial site (Mukhopadhyay et al. 2002). The endothelium-dependent component was found to be SR141716-sensitive and also to involve pertussis toxin (PTX)-sensitive G proteins and NO production, whereas the endothelium-independent minor component appeared to be via a PTX-insensitive mechanism involving TRPVl receptors, CGRP, and NO... 

Anandamide is proposed as an endogenous cannabinoid that has been shown to mimic the effects of tetrahydrocannabinol in both in vivo and in vitro systems. Thus, THC and anandamide have common pharmacological properties despite their different structures. The former is a rigid compound whereas the latter is flexible. 

What is, then, the biogenesis of anandamide One of the aims of the present chapter is to review the last three years of research in this area and provide a possible answer to this question. I will also briefly describe what is currently known on other aspects of anandamide metabolism in brain tissue, in particular its hydrolytic degradation and oxygenation by lipoxygenase enzymes. Before we address these issues, however, it will be useful to review the biological effects of anandamide in the wider context of the multiple pharmacological properties of plant-derived and synthetic cannabinoid drugs. 

The chemical synthesis of anandamide confirmed this structural identification, and allowed Mechoulam, Devane and their colleagues to determine its pharmacological properties. In vitro and in vivo tests showed a great similarity of effects between anandamide and cannabinoid drugs. Anandamide reduced the electrogenic contraction of mouse vas deferens and, most importantly, closely mimicked the behavioral responses induced by... 

Subsequently, the pharmacological properties of anandamide have been explored in considerable detail and by using a variety of experimental models, all of which have confirmed and extended the validity of the early observations. There is now little doubt that anandamide is an endogenous lipid component present in the brain, which activates CBl cannabinoid receptors. Although anandamide binds also to peripheral CB2 receptors, it does so with a much lower affinity than to CBl. Moreover, its ability to activate the CB2 subtype remains controversial, and a role as endogenous CB2 receptor antagonist has been proposed. 

We also need to learn more about the effects of anandamide on the electrical properties of central neurons. Thus far, the elec-trophysiological actions of anandamide have been studied for the most part using heterologous expression systems. These are of course useful pharmacological models, but they bear little resemblance to the functionally diverse neurons which constitute the adult mammalian central nervous system. 

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